B cell memory is a multi-faceted cellular process whose main purpose is long-term immune protection targeted to previously experienced antigens. While humoral immunity is considered the most substantial barrier to antigen re-challenge, the cellular underpinnings of this important protective mechanism remain poorly understood. My laboratory focuses on helper T (Th) cell- regulated B cell immunity and seeks to understand the cellular and molecular mechanisms that regulate the development of antigen-specific B cell memory in vivo. We hypothesize that B cell memory is organized into multiple cellular compartments, developmentally distinct and functionally sub-specialized to provide long-term antigen-specific protection. During the initial funding period, we provided evidence for two separable compartments of antigen- specific memory B cells based on antigen-binding, isotype-switch, BCR expression, BCR co- receptor expression (CD79b), differential cell surface phenotype, cellular dynamics in vivo, presence of mutated mRNA for Ig genes and adoptive transfer of antigen responsiveness. These data allowed us to propose a linear progression of development for antigen-specific B cell memory. This model suggests that germinal centers export 'post-GC'6B2+ CD79b+ memory B cells that give rise to distinct and persistent 'pre-plasma'6B2neg CD79b+ memory B cells, the cellular precursors of CD138+ long-lived plasma cells (PC). The developmental defect in 6B2neg CD79b+ memory compartment and loss of CD138+ plasma cells in mice with a conditional deletion of Blimp-1 was consistent with this model. We will pursue these studies across two specific aims to determine unambiguously the origins of the memory B cell subsets (SA#1) and to examine what mechanisms regulate their development, survival and reactivation in vivo (SA#2).